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Thursday, May 24, 2012

CMT4 Next Steps

Next Steps

After learning that Stacy likely has a compound heterozygote mutation causing CMT4, I found out that SH3TC2 is a known CMT4 causal gene causing CMT4C. I decided to investigate what we know about SH3TC2 and CMT4 in general. My search led me to find out about the work being done by the CMTA (CMT Association). In 2010, the CMTA, working together with the NIH, finished testing ~350,000 compounds at 7 different dosage levels in the effort to find a treatment for CMT1A. CMT1A is somewhat related, but still different from CMT4C. CMT1A is caused by overexpression of the PMP22 gene whereas CMT4C is caused by having no functional copies of the SH3TC2 gene. Now that we have found the causal gene, I researched the state-of-the-art of CMT4 research. The following describes where CMT4 is in terms of developing a therapeutic intervention.

CMT4 Is A Rare Disease

About 1 out of 2500 have CMT. Out of everyone with CMT, the vast majority have a subtype of CMT1. CMT2 is less common, and CMT4 is the least common. Proper estimates are difficult to ascertain. Since CMT4 is genetic and autosomal recessive, sub-populations of people can have high incidence rates and CMT4 may appear to sporadically occur within a population. A study published in Jan 2011 estimates that CMT4 accounts for 1.4% of all CMT cases (Saporta et al., 2011). However, this reflects what was observed in a single clinic and the same study performed in a foreign country or even another state would likely yield very different numbers. It is also entirely possible for CMT4 to be under-diagnosed due to lack of genetic testing. Estimates of the number of people who are carriers for the recessive mutations causing CMT4 across worldwide populations would help produce a more accurate estimate.

Still, there is no denying that CMT4 is rare even compared to other types of CMT. This means that CMT4 is unlikely to ever be targeted by pharmaceutical companies. Drug discovery is an expensive and laborious process. If a company is ever going to recover the initial investment as well as make a profit, they need a large number of people who have a disease. I don't see harm in companies like Pfizer investing enormous amounts of money over nearly a decade and financing trials on over 3,000 women in order to test Viagra for women (Gardiner Harris, 2004). In the end, we all benefit from research that may not appear at first glance to have serious importance or value. I certainly do not deny that Viagra addresses a serious problem, in spite of its reputation. Ultimately, self-sustaining drug research to alter any phenotype greatly adds to our knowledge and helps refine the drug discovery process for disease. Unfortunately, CMT4 is definitely very rare and if we are ever going to make progress, it will take a combination of governmental, academic, private donations, and non-profit institutions as they aren't generally driven by profit.

The Charcot Marie Tooth Association

The CMTA has been doing some truly amazing work for CMT1A. In 2010, the NIH working in conjunction with CMTA announced the completion of a high-throughput screening program. They tested ~350,000 compounds at 7 different dosage levels for a total of over 2 million unique screens. As a result, they identified 810 compounds that may help people who have CMT1A . Of these 810 compounds, 10 are FDA approved (Dana Schwertfeger, 2010). Since then, they have zeroed in on 3 FDA approved compounds. The CMTA has moved forward with testing 2 of these 3 FDA approved compounds at two different dosage levels for a total cost of $400,000 at $100,000 per dose (Herb Beron, 2012). The pharmaceutical industry has been making progress as well. Pharnext has begun a Phase II clinical trial for a drug (which is actually a combination of 3 drugs) to treat CMT1A (Pharnext Press Release 2010).

The single overarching principle is to find a compound that lowers the expression of the PMP22 gene, which is duplicated or overly expressed in people with CMT1A. Unfortunately, this doesn't do much  for people like Stacy who have CMT4. I will get into the details of what goes wrong with CMT4 in later posts, but it has to do with having no working copy of the SH3TC2 gene.

CMT2A and CMT2E are next for CMTA

Recently, the CMTA received a large private donation earmarked for CMT2A and CMT2E that has enabled them to move forward with developing the cellular assays necessary for implementing the same high-throughput drug screening approach used for CMT1A (Herb Beron, 2012). It's great to see the  CMTA  moving on to different types of CMT now that CMT1A has entered a new phase in the development of a therapeutic intervention. I have no doubt that that people who have CMT1A and CMT2A will eventually benefit tremendously from the amazing work that is being coordinated by the CMTA.

What About CMT4?

CMT4 is an "orphan disease". It will not be adopted by the pharmaceutical industry as there is no financial incentive to treat or prevent it. Unfortunately, there is also currently no plan to implement high-throughput drug screening for CMT4 by any non-profit organization. Moving forward with developing cellular assays and high-throughput drug screening is expensive and this is a rare disease. This underscores the need for organizations outside of the profit-driven pharmaceutical industry to move forward on orphan diseases like CMT4. While a private corporation like Pharnext is already testing CMT1A in Phase II clinical trials, it is extremely doubtful that they will attempt to treat CMT4 in the future. CMT4 is rare and profit will likely never be the reason treatments are developed. Research via non-profit, academic, private donations, and governmental institutions is the only way orphan diseases like CMT4 will ever see therapeutic intervention.

I am currently researching how feasible it is to finance and perform single compound drug screening for CMT4. While a high-throughput approach is preferable and more likely to yield results, it is possible to prioritize compounds and test a few at lower cost. As before, I intend to publicize everything I learn in order to make this entire project as transparent as possible. The first goal (Phase I) was to determine Stacy's CMT subtype and was successful. The next phase of the project will be explained in more detail in future posts, but involves prioritizing compounds for treatment of CMT4.


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